Tempi di accesso ai farmaci in Italia nel periodo 2015-2017: analisi delle tempistiche di valutazione dell'Agenzia Italiana del Farmaco

Objectives: To describe the length of time taken by the Italian Medicines Agency (AIFA) to formulate pricing and reimbursement decisions for drugs approved via centralized procedures and to evaluate possible differences between categories of drugs (innovative drugs, oncological and rare disease drugs, products negotiated with Managed Entry Agreements and/or managed via registry). Methods: Monthly meeting reports of the Technical Scientific Committee (CTS) and the Price and Reimbursement Committee (CPR) as well European and Italian Official Journals were scrutinized from January 2015 to January 2018. Results: In the scrutinized period, 85 out of 190 drugs obtained reimbursement and were included in the analysis. Overall, time-to-market (CTS assessment opening to Official Journal) was 258 days. About one third of the whole procedure was dedicated to administrative steps, without significant differences between drug categories. Conclusions: Our analysis shows that transparency makes it possible to determine the length of time taken by AIFA to conclude the Price and Reimbursement (P&R) process. It also suggests that administrative procedures may still be optimized to allow faster access to treatments for patients and provides a starting point to determine future policies in this area

Pseudomonas populations causing pith necrosis of tomato and pepper in Argentina are highly diverse

Pseudomonas species causing pith necrosis symptoms on tomato and pepper collected in different areas of Argentina were identified as Pseudomonas corrugata, P. viridiflava and Pseudomonas spp. Their diversity was analysed and compared with reference strains on the basis of their phenotypic characteristics, copper and antibiotic sensitivity tests, serology, pathogenicity, DNA fingerprinting and restriction fragment length polymorphism (RFLP) analysis of a 16S rRNA gene fragment. All P. corrugata strains tested were copper-resistant while P. viridiflava strains were more variable. Numerical analysis of phenotypic data showed that all P. corrugata strains formed a single phenon that clustered at a level of about 93%, while all the P. viridiflava strains clustered in a separated phenon at a level of 94%. Genomic analysis by repetitive (rep)-PCR and 16S rRNA-RFLP fingerprinting and serological analysis showed that the two species contained considerable genetic diversity. Inoculations of tomato and pepper plants with strains from both hosts caused similar pith necrosis symptoms. Strains of both P. corrugata and P. viridiflava were grouped according to their geographical origin and not according to the original host. This is the first report of Pseudomonas viridiflava causing pith necrosis on pepper.Facultad de Ciencias Agrarias y ForestalesInstituto de Biotecnologia y Biologia Molecula

Pseudomonas populations causing pith necrosis of tomato and pepper in Argentina are highly diverse

Pseudomonas species causing pith necrosis symptoms on tomato and pepper collected in different areas of Argentina were identified as Pseudomonas corrugata, P. viridiflava and Pseudomonas spp. Their diversity was analysed and compared with reference strains on the basis of their phenotypic characteristics, copper and antibiotic sensitivity tests, serology, pathogenicity, DNA fingerprinting and restriction fragment length polymorphism (RFLP) analysis of a 16S rRNA gene fragment. All P. corrugata strains tested were copper-resistant while P. viridiflava strains were more variable. Numerical analysis of phenotypic data showed that all P. corrugata strains formed a single phenon that clustered at a level of about 93%, while all the P. viridiflava strains clustered in a separated phenon at a level of 94%. Genomic analysis by repetitive (rep)-PCR and 16S rRNA-RFLP fingerprinting and serological analysis showed that the two species contained considerable genetic diversity. Inoculations of tomato and pepper plants with strains from both hosts caused similar pith necrosis symptoms. Strains of both P. corrugata and P. viridiflava were grouped according to their geographical origin and not according to the original host. This is the first report of Pseudomonas viridiflava causing pith necrosis on pepper.Facultad de Ciencias Agrarias y ForestalesInstituto de Biotecnologia y Biologia Molecula

Pseudomonas populations causing pith necrosis of tomato and pepper in Argentina are highly diverse

Pseudomonas species causing pith necrosis symptoms on tomato and pepper collected in different areas of Argentina were identified as Pseudomonas corrugata, P. viridiflava and Pseudomonas spp. Their diversity was analysed and compared with reference strains on the basis of their phenotypic characteristics, copper and antibiotic sensitivity tests, serology, pathogenicity, DNA fingerprinting and restriction fragment length polymorphism (RFLP) analysis of a 16S rRNA gene fragment. All P. corrugata strains tested were copper-resistant while P. viridiflava strains were more variable. Numerical analysis of phenotypic data showed that all P. corrugata strains formed a single phenon that clustered at a level of about 93%, while all the P. viridiflava strains clustered in a separated phenon at a level of 94%. Genomic analysis by repetitive (rep)-PCR and 16S rRNA-RFLP fingerprinting and serological analysis showed that the two species contained considerable genetic diversity. Inoculations of tomato and pepper plants with strains from both hosts caused similar pith necrosis symptoms. Strains of both P. corrugata and P. viridiflava were grouped according to their geographical origin and not according to the original host. This is the first report of Pseudomonas viridiflava causing pith necrosis on pepper.Facultad de Ciencias Agrarias y ForestalesInstituto de Biotecnologia y Biologia Molecula

Primary Biliary Cholangitis : advances in management and treatment of the disease

Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10\uc2\ua0year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer. Ursodeoxycholic acid is the only treatment available today, but even if effective in counteracting the disease progression for the majority of patients, in approximately 40% is not able to decrease effectively the alkaline phosphatase, a surrogate marker of disease activity. Recently, obeticholic acid received the European Medicines Agency conditional approval, as add on treatment in patients non responders or intolerant to ursodeoxycholic acid. The present paper illustrates the opinion of a working group, composed by clinical pharmacologists, gastroenterologists/hepatologists with specific expertise on Primary Biliary Cholangitis and patient associations, on the state of the art and future perspectives of the disease management. The agreement on the document was reached through an Expert Meeting

Liderazgo directivo y desempeño docente en el nivel secundario de la Institución Educativa San Luís Gonzaga del Distrito de Ancahuasi - Anta- Cusco - 2017

TesisEl presente trabajo de investigación tiene como objetivo principal determinar la relación lineal entre el liderazgo directivo y el desempeño docente en el nivel secundario de la institución educativa San Luis Gonzaga del distrito de Ancahuasi - Anta- Cusco – 2017. Tanto la encuesta sobre liderazgo directivo como la ficha de evaluación del desempeño docente fueron aplicadas sobre toda la población conformada por 30 profesores sin exclusión y al equipo directivo. Se obtuvieron como resultados la no correlación entre los aspectos estudiados y se concluye que el desempeño docente está vinculado a diversos factores, tales como: clima organizacional, cultura escolar, situación económica, clima escolar, capacitaciones, condición del personal entre otros, y que la percepción del liderazgo ejercido por el director es sólo un aspecto más. Se incl. uye un análisis descriptivo comparativo con los aspectos sociodemográficos considerados, tales como edad, género, estado civil, tiempo de servicios, área de enseñanza y otros

Price and reimbursement of advanced therapeutic medicinal products in Europe: are assessment and appraisal diverging from expert recommendations?

Background: Advanced therapy medicinal products (ATMPs) represent an important cornerstone for innovation in healthcare. However, uncertainty on the value, the high average cost per patient and their one-shot nature has raised a debate on their assessment and appraisal process for pricing and reimbursement (P&R) purposes. This debate led experts providing for recommendations on this topic. Our primary objective is to investigate the ATMPs P&R process in the main five European countries and to understand if this process is consistent with published P&R expert recommendations. We also investigated the current ATMP pipelines to understand if future ATMPs will create challenges for their P&R process. Methods: P&R framework for ATMPs in the European Major five (EU5) countries was investigated through a literature search on PubMed, institutional websites of National Health Authorities and grey literature. The ATMPs pipeline database was populated from a clinical trial database (clinicaltrials.gov), relying on inclusion and exclusion criteria retrieved from the literature. Results: Reimbursement status of ATMPs is different across the EU5 countries, with the exception of CAR-Ts which are reimbursed in all countries. Standard P&R process in place for other medicinal products is extended to ATMPs, with the exception of some cases in Germany. List prices, where available, are high and, tend to be aligned across countries. Outcome-based Managed Entry Agreements (MEAs) have been extensively used for ATMPs. Extra-funds for hospitals managing ATMPs were provided only in Germany and, as additional fund per episode, in France. The accreditation process of hospitals for ATMPs management was in most countries managed by the national authorities. As far as ATMPs pipeline is concerned, ATMPs in development are mostly targeting non-rare diseases. Conclusions: Expert recommendations for ATMPs P&R were partially applied: the role of outcome-based MEAs has increased and the selection process of the centres authorized to use these treatments has been enhanced; additional funding for ATMPs management to accredited centres has not been completely considered and annuity payment and broader perspective in cost considerations are far from being put in place. These recommendations should be considered for future P&R negotiations to pursue rational resource allocation and deal with budget constraints

Differential deregulation of astrocytic calcium signalling by amyloid-β, TNFα, IL-1β and LPS

In Alzheimer's disease (AD), astrocytes undergo complex morphological and functional changes that include early atrophy, reactive activation and Ca(2+) deregulation. Recently, we proposed a mechanism by which nanomolar A\u3b242 deregulates mGluR5 and InsP3 receptors, the key elements of astrocytic Ca(2+) signalling toolkit. To evaluate the specificity of these changes, we have now investigated whether the effects of A\u3b242 on Ca(2+) signalling machinery can be reproduced by pro-inflammatory agents (TNF\u3b1, IL-1\u3b2, LPS). Here we report that A\u3b242 (100nM, 72h) significantly increased mRNA levels of mGluR5, InsP3R1 and InsP3R2, whereas pro-inflammatory agents reduced expression of these specific mRNAs. Furthermore, DHPG-induced Ca(2+) signals and store operated Ca(2+) entry (SOCE) were augmented in A\u3b242-treated cells due to up-regulation of a set of Ca(2+) signalling-related genes including TRPC1 and TRPC4. Opposite changes were observed when astrocytes were treated with TNF\u3b1, IL-1\u3b2 and LPS. Last, the effects observed on SOCE by treating wild-type astrocytes with A\u3b242 were also identified in untreated astrocytes from 3 7Tg-AD animals, suggesting a link to the AD pathology. Our results demonstrate that effects of A\u3b242 on astrocytic Ca(2+) signalling differ from and may contrast to the effects of pro-inflammatory agents

A novel Ca2+-mediated cross-talk between endoplasmic reticulum and acidic organelles: Implications for NAADP-dependent Ca2+ signalling

Nicotinic acid adenine dinucleotide phosphate (NAADP) serves as the ideal trigger of spatio-temporally complex intracellular Ca(2+) signals. However, the identity of the intracellular Ca(2+) store(s) recruited by NAADP, which may include either the endolysosomal (EL) or the endoplasmic reticulum (ER) Ca(2+) pools, is still elusive. Here, we show that the Ca(2+) response to NAADP was suppressed by interfering with either EL or ER Ca(2+) sequestration. The measurement of EL and ER Ca(2+) levels by using selectively targeted aequorin unveiled that the preventing ER Ca(2+) storage also affected ER Ca(2+) loading and vice versa. This indicates that a functional Ca(2+)-mediated cross-talk exists at the EL-ER interface and exerts profound implications for the study of NAADP-induced Ca(2+) signals. Extreme caution is warranted when dissecting NAADP targets by pharmacologically inhibiting EL and/or the ER Ca(2+) pools. Moreover, Ca(2+) transfer between these compartments might be essential to regulate vital Ca(2+)-dependent processes in both organelles